Abstract 1764: Cross-Talk between Cardiac Mast Cells and Fibroblasts Contributes to Myocardial Fibrosis in a Transgenic Model of Inflammatory Cardiomyopathy
Previous studies have shown that mice with cardiac restricted overexpression of tumor necrosis factor (sTNF mice), an inflammatory mediator, develop progressive myocardial fibrosis and adverse cardiac remodeling. However the mechanism for the cardiac fibrosis is not understood, in that TNF does not directly stimulate fibroblasts to synthesize collagen. Noting that mast cells accumulate in and around areas of ongoing tissue fibrosis, we sought to test the hypothesis that TNF-induced fibrosis is mediated indirectly via TNF-induced recruitment of mast cells to the heart, and that the recruited mast cells activate fibroblasts to synthesize collagen. Mast cell number increased 2–3-fold (p < 0.01) at 8–12 weeks in sTNF mice compared to littermate (LM) controls. FACS analysis showed there was a significant (p < 0.01) 2-fold increase in CD40 expression, a marker of fibroblast activation, on isolated sTNF fibroblasts compared to isolated LM fibroblasts. The mast cell derived ligand that binds to CD40, CD154, was also strikingly increased in sTNF hearts, whereas CD154 was not detectable in LM hearts. To test the significance of these findings we crossed sTNF mice with mast cell deficient (MC−/−) mice, and examined the hearts from sTNF, MC−/−/sTNF, and LM control mice histologically at 4, 8, and 12 weeks. There was a significant increase in collagen volume fraction (Picrosirius Red staining) in sTNF mice compared to LM at 4 (5.9-fold, p < 0.004), 8 (3.6-fold, p < 0.0001), and 12 (11-fold, p < 0.0001) weeks that was significantly attenuated in the MC−/−/sTNF mice at 4 and 8 weeks of age, and was abrogated by 12 weeks of age. Taken together, these results suggest that the progressive myocardial fibrosis in inflammatory cardiomyopathies is modulated, at least in part, by recruitment of mast cells to areas of inflammation, and that cross-talk between mast cells and fibroblasts contributes to the pathological myocardial fibrosis observed in inflammatory cardiomyopathies.